1. Medicine
Download icon

Mechanisms underlying neonate specific metabolic effects of volatile anesthetics

Research Article
  • Cited 0
  • Views 524
  • Annotations
Cite this article as: eLife 2021;10:e65400 doi: 10.7554/eLife.65400

Abstract

Volatile anesthetics (VAs) are widely used in medicine, but the mechanisms underlying their effects remain ill-defined. Though routine anesthesia is safe in healthy individuals, instances of sensitivity are well-documented, and there has been significant concern regarding the impact of VAs on neonatal brain development. Evidence indicates that VAs have multiple targets, with anesthetic and non-anesthetic effects mediated by neuroreceptors, ion channels, and the mitochondrial electron transport chain. Here, we characterize an unexpected metabolic effect of VAs in neonatal mice. Neonatal blood β-hydroxybutarate (β-HB) is rapidly depleted by VAs at concentrations well below those necessary for anesthesia. β-HB in adults, including animals in dietary ketosis, is unaffected. Depletion of β-HB is mediated by citrate accumulation, malonyl-CoA production by acetyl-CoA carboxylase, and inhibition of fatty acid oxidation. Adults show similar significant changes to citrate and malonyl-CoA, but are insensitive to malonyl-CoA, displaying reduced metabolic flexibility compared to younger animals.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Julia Stokes

    CIBR, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    No competing interests declared.
  2. Arielle Freed

    CIBR, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    No competing interests declared.
  3. Rebecca Bornstein

    Pathology, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
  4. Kevin N Su

    Pathology, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
  5. John Snell

    CIBR, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    No competing interests declared.
  6. Amanda Pan

    CIBR, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    No competing interests declared.
  7. Grace X Sun

    CIBR, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    No competing interests declared.
  8. Kyung Yeon Park

    CIBR, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    No competing interests declared.
  9. Sangwook Jung

    CIBR, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    No competing interests declared.
  10. Hailey Worstman

    CIBR, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    No competing interests declared.
  11. Brittany M Johnson

    CIBR, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    No competing interests declared.
  12. Philip G Morgan

    Anesthesia and Pain Medicine, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4857-2756
  13. Margaret M Sedensky

    Anesthesia and Pain Medicine, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
  14. Simon C Johnson

    Neurology, University of Washington, Seattle, United States
    For correspondence
    simoncj@u.washington.edu
    Competing interests
    Simon C Johnson, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1942-3674

Funding

NIH Office of the Director (R01GM133865)

  • Margaret M Sedensky
  • Simon C Johnson

NIH Office of the Director (R01GM118514)

  • Philip G Morgan
  • Simon C Johnson

NIH Office of the Director (R00GM126147)

  • Simon C Johnson

Northwest Mitochondrial Research Guild

  • Simon C Johnson

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (Sedensky IACUC00070) at Seattle Children's Research Institute. The protocol was approved by the Committee on the Ethics of Animal Experiments at Seattle Children's Research Institute. Every effort was made to minimize suffering.

Reviewing Editor

  1. Carlos Isales, Medical College of Georgia at Augusta University, United States

Publication history

  1. Received: December 3, 2020
  2. Preprint posted: December 9, 2020 (view preprint)
  3. Accepted: July 12, 2021
  4. Accepted Manuscript published: July 13, 2021 (version 1)
  5. Version of Record published: July 20, 2021 (version 2)

Copyright

© 2021, Stokes et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 524
    Page views
  • 57
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Medicine
    Mieradilijiang Abudupataer et al.
    Research Article Updated

    Background:

    Bicuspid aortic valve (BAV) is the most common congenital cardiovascular disease in general population and is frequently associated with the development of thoracic aortic aneurysm (TAA). There is no effective strategy to intervene with TAA progression due to an incomplete understanding of the pathogenesis. Insufficiency of NOTCH1 expression is highly related to BAV-TAA, but the underlying mechanism remains to be clarified.

    Methods:

    A comparative proteomics analysis was used to explore the biological differences between non-diseased and BAV-TAA aortic tissues. A microfluidics-based aorta smooth muscle-on-a-chip model was constructed to evaluate the effect of NOTCH1 deficiency on contractile phenotype and mitochondrial dynamics of human aortic smooth muscle cells (HAoSMCs).

    Results:

    Protein analyses of human aortic tissues showed the insufficient expression of NOTCH1 and impaired mitochondrial dynamics in BAV-TAA. HAoSMCs with NOTCH1-knockdown exhibited reduced contractile phenotype and were accompanied by attenuated mitochondrial fusion. Furthermore, we identified that mitochondrial fusion activators (leflunomide and teriflunomide) or mitochondrial fission inhibitor (Mdivi-1) partially rescued the disorders of mitochondrial dynamics in HAoSMCs derived from BAV-TAA patients.

    Conclusions:

    The aorta smooth muscle-on-a-chip model simulates the human pathophysiological parameters of aorta biomechanics and provides a platform for molecular mechanism studies of aortic disease and related drug screening. This aorta smooth muscle-on-a-chip model and human tissue proteomic analysis revealed that impaired mitochondrial dynamics could be a potential therapeutic target for BAV-TAA.

    Funding:

    National Key R and D Program of China, National Natural Science Foundation of China, Shanghai Municipal Science and Technology Major Project, Shanghai Science and Technology Commission, and Shanghai Municipal Education Commission.

    1. Medicine
    Elisabeth Gludovacz et al.
    Research Article Updated

    Background:

    Excessive plasma histamine concentrations cause symptoms in mast cell activation syndrome, mastocytosis, or anaphylaxis. Anti-histamines are often insufficiently efficacious. Human diamine oxidase (hDAO) can rapidly degrade histamine and therefore represents a promising new treatment strategy for conditions with pathological histamine concentrations.

    Methods:

    Positively charged amino acids of the heparin-binding motif of hDAO were replaced with polar serine or threonine residues. Binding to heparin and heparan sulfate, cellular internalization and clearance in rodents were examined.

    Results:

    Recombinant hDAO is rapidly cleared from the circulation in rats and mice. After mutation of the heparin-binding motif, binding to heparin and heparan sulfate was strongly reduced. The double mutant rhDAO-R568S/R571T showed minimal cellular uptake. The short α-distribution half-life of the wildtype protein was eliminated, and the clearance was significantly reduced in rodents.

    Conclusions:

    The successful decrease in plasma clearance of rhDAO by mutations of the heparin-binding motif with unchanged histamine-degrading activity represents the first step towards the development of rhDAO as a first-in-class biopharmaceutical to effectively treat diseases characterized by excessive histamine concentrations in plasma and tissues.

    Funding:

    Austrian Science Fund (FWF) Hertha Firnberg program grant T1135 (EG); Sigrid Juselius Foundation, Medicinska Understödsförening Liv och Hälsa rft (TAS and SeV).